Mechanisms in Cancer Evolution Program (MCEP) PROJECT SUMMARY The mission of the Mechanisms in Cancer Evolution Program (MCEP) at the DLDCCC is focused on understanding molecular mechanisms that generate heterogeneity (genetic and non-genetic or epi-genetic) and environmental drivers that spur evolution of cancers. Evolution occurs by variation, which creates heterogeneity and selection. Heterogeneity is generated by intrinsic genomic and non-genetic phenotype-plasticity mechanisms, as well as by alteration of cellular programs by extrinsic viruses, the microbiome, and nutritional modulation. The goal of the MCEP is fundamental basic science discovery of how these molecular mechanisms work. New paradigms discovered can open new translational directions (throughout the DLDCCC Programs and by others), including novel evolutionary biomarkers, diagnostic, preventative, and therapeutic tools. For example, whereas conventional therapies kill cells or stop them from growing (are anti-proliferative), proposed novel interventions that would slow evolution, promise new and fundamentally different ways to inhibit oncogenesis and thwart resistance. Also, identification of biomarkers of highly evolvable cells may allow detection of at-risk individuals, and earlier detection of cancers. The MCEP currently has 26 members: 25 are Research members from the BCM Departments of Molecular and Human Genetics, Molecular Virology and Microbiology, Biochemistry and Molecular Biology, Pediatrics-Oncology, Medicine-Infectious Disease, Pathology and Immunology, and the Huffington Center on Aging; one is an adjunct member, appointed at the University of Texas, Austin. Members of the MCEP published a total of 576 cancer-related papers in the previous funding period with 25% in journals with Impact Factors of 10 or above. Of the 576 manuscripts, 11% represented intra- programmatic, 46% inter-programmatic, and 68% inter-institutional collaborations. The MCEP currently has a total of $10.5 million in selected cancer-relevant funding (direct costs per annum), which includes $2 million from NCI, $5.8 million in other NIH funding and $2.2 million in other peer reviewed funding mostly from the Cancer Prevention and Research Initiative of Texas (CPRIT). The two MCEP Aims encompass mechanisms of promotion of heterogeneity by: (1) Intrinsic Evolution Promoters (mutation, genome rearrangement, recombination, epigenetic heritable protein- and RNA-error-mediated variation); and (2) Extrinsic Evolution Promoters, including viruses, microbes generally, the microbiome, and nutritional modulators of both host and microbiome. The CCSG supports this Research Program by providing key Shared Resources, particularly High- Parameter Flow Cytometry; Advanced Microscopy and Image Informatics; Genomic, Transcriptomic, Epigenomic and Single-Cell, Metabolomics, and Proteomics; as well as administrative support for meetings, clubs and interest groups, and pilot funding and recruitment funds.